Respiratory tract infections are common infections of the upper respiratory tract (e.g., nose, ears, sinuses, and throat) and lower respiratory tract (e.g., trachea, bronchial tubes, and lungs). Symptoms of upper respiratory tract infection include runny or stuffy nose, irritability, restlessness, poor appetite, decreased activity level, coughing, and fever.
Viral respiratory tract infections cause and/or are associated with sore throats, colds, croup, and the flu. Examples of viruses that cause upper and lower respiratory tract infections include rhinoviruses and influenza viruses A and B.
Common respiratory bacterial infections cause and/or associated with, for example, whooping cough and strep throat. An example of a bacterium that causes upper and lower respiratory tract infections is Streptococcus pneumoniae, Streptococcus pneumoniae (pneumococcus) causes respiratory tract infections among infants and the elderly worldwide. Capsular polysaccharide is the main virulence factor, and its composition defines 91 serotypes of pneumococcus. Certain serotypes colonize asymptomatically the human nasopharynx representing a reservoir for inter-individual transmission of the bacteria. In some individuals colonization may progress to pneumococcal pneumonia and invasive disease. In contrast, serotypes like serotype 1 are rarely associated with colonization but cause invasive infections.
Current therapies for respiratory tract infections involve the administration of anti-viral agents, anti-bacterial, and antifungal agents for the treatment, prevention, or amelioration of viral, bacterial, and fungal respiratory tract infections, respectively. Unfortunately, in regard to certain infections, there are no therapies available, infections have been proven to be refractory to therapies, or the occurrence of side effects outweighs the benefits of the administration of a therapy to a subject. The use of anti-bacterial agents for treatment of bacterial respiratory tract infections may also produce side effects or result in resistant bacterial strains. The administration of antifungal agents may cause renal failure or bone marrow dysfunction and may not be effective against fungal infection in subjects with suppressed immune systems. Additionally, the infection causing microorganism (e.g., virus, bacterium, or fungus) may be resistant or develop resistance to the administered therapeutic agent or combination of therapeutic agents. In fact, microorganisms that develop resistance to administered therapeutic agents often develop pleiotropic drug or multidrug resistance, that is, resistance to therapeutic agents that act by mechanisms different from the mechanisms of the administered agents. Thus, as a result of drug resistance, many infections prove refractory to a wide array of standard treatment protocols.
Therefore, new therapies for the treatment, prevention, management, and/or amelioration of respiratory tract infections and symptoms thereof are needed.
Activation of innate defences is essential to control pneumococcal infection. Toll-like receptor 2 (TLR2), TLR4 and TLR9 as well as the adaptor MyD88 participate in the early detection and clearance of pneumococcus in the lungs. The cytosolic receptors nucleotide-binding oligomerization domain (Nod) containing Nod1 and Nod2, have also been involved in the recognition of pneumococci. TLR signaling activates mucosal innate responses that culminate with the recruitment of phagocytes like polymorphonuclear neutrophils (PMN) and macrophages and the production of microbicidal agents. This process triggers rapid eradication of the pathogen by phagocytosis as well as extracellular killing. In MyD88-deficient animals S. pneumoniae is unable to intrinsically trigger any PMN recruitment into airways and animals have increased susceptibility to pneumonia. The contribution of TLR signaling in humans has been highlighted by a recent study showing that some MyD88 polymorphisms are associated with increased susceptibility to pneumococcal infection.
Modulating immunity by the activity of innate receptors is an emerging concept to elicit protective responses against infections. The rationale is to promote innate responses that greatly exceed in magnitude, quality and dynamic the innate response triggered by the pathogen itself. The effectiveness of TLR agonists for therapeutic treatment of infectious diseases has been demonstrated in several animal models, including models of respiratory tract infections (Brown, K. L., C. Cosseau, J. L. Gardy and R. E. Hancock 2007. Complexities of targeting innate immunity to treat infection. Trends Immunol 28:260-266; Lembo, A., M. Pelletier, R. Iyer, M. Timko, J. C. Dudda, T. E. West, C. B. Wilson, A. M. Hajjar, and S. J. Skerrett. 2008. Administration of a synthetic TLR4 agonist protects mice from pneumonic tularemia. J Immunol 180:7574-7581; Romagne, F. 2007. Current and future drugs targeting one class of innate immunity receptors: the Toll-like receptors. Drug Discov Today 12:80-87). TLR5 senses bacterial flagellins that are the main constituent of flagella. Various cells of the pulmonary tract including the epithelial cells express TLR5 but the modulation of the TLR5 signalling pathway has not yet been investigated for the treatment of respiratory tract infections.